Bottom Line:
Rats in both the 5- and 90-second groups pressed more on the active versus inactive lever following extensive (24 sessions) but not following limited (3 sessions) self-administration training.There were no group differences in this behaviour.However, the rewarding properties of the cues were not "forgotten" because on withdrawal days 32-33, amphetamine selectively enhanced active-lever pressing, and did so to a similar extent in both groups.

ABSTRACTThe faster drugs of abuse reach the brain, the more addictive they can be. It is not known why this is. Environmental stimuli associated with drugs can promote the development and persistence of addiction by invigorating and precipitating drug-seeking behaviour. We determined, therefore, whether cues associated with the self-administration of rapidly delivered cocaine (injected intravenously over 5 versus 90 seconds) would acquire greater conditioned rewarding properties, as assessed by the performance of an operant response reinforced solely by the cues. Rats nose-poked for intravenous cocaine infusions delivered either over 5 or 90 seconds. Discrete visual cues accompanied each infusion. The rats could then press a lever to obtain the cues--now a conditioned reward--or an inactive lever. Rats in both the 5- and 90-second groups pressed more on the active versus inactive lever following extensive (24 sessions) but not following limited (3 sessions) self-administration training. There were no group differences in this behaviour. Following withdrawal from cocaine self-administration, lever discrimination progressively abated in both groups and was lost by withdrawal day 30. However, the rewarding properties of the cues were not "forgotten" because on withdrawal days 32-33, amphetamine selectively enhanced active-lever pressing, and did so to a similar extent in both groups. Thus, cues paired with rapid or slower cocaine delivery acquire similar conditioned rewarding properties. We conclude, therefore, that the rapid delivery of cocaine to the brain promotes addiction by mechanisms that might not involve a greater ability of drug cues to control behaviour.

pone-0026481-g005: In Experiment 2, there were no differences in the amount of cocaine exposure, cocaine-cue exposure, or the number of days to reach each ratio/infusion criterion between the 5- and 90-s groups.Total drug intake (panel A), number of cue-cocaine pairings (panel B) and days to reach ratio/infusion criteria (panel C) in the 5- and 90-s groups. Rats were required to meet the FR 1 and FR 2 criteria as well as infusion criteria 10–15 for 2 days each, and to meet infusion criterion 20 for 21 days. Values are mean ± SEM. n's = 6–7/group. s, seconds. CS, conditioned stimulus; UCS; unconditioned stimulus. FR; fixed ratio.

Mentions:
In experiment 2, rats were trained to nose-poke for cocaine delivered either over 5 or 90 s, with an 85-s time out period for the 5-s group, first under an FR 1 schedule, and then under FR 2. Acquisition criteria were defined as taking ≥5 infusions/session, at regular intervals throughout the session. Acquisition criteria had to be met for two consecutive days under each ratio schedule. Next, rats were allowed to self-administer cocaine infusions delivered either over 5 or 90 s and accompanied by light cues. During this phase, the rats were required to meet a criterion of 10 and then 15 infusions/session, for 2 consecutive days each, and then an infusion criterion of 20 for 21 days. Figure 5 shows the total amount of cocaine consumed (A), the total number of cue-cocaine pairings earned (B) and the number of days to reach each ratio and infusion criterion (C) by rats in the 5- and 90-s groups. There was no group difference in the total quantity of cocaine consumed [(A), t(11) = 0.19, p = 0.85] or the total number of cue-cocaine pairings earned [(B), t(11) = 0.24, p = 0.82]. In addition, there were no group differences in the mean ± SEM number of days to meet each ratio and infusion criterion [(C), F(1, 11) = 0.58, p = 0.46].

pone-0026481-g005: In Experiment 2, there were no differences in the amount of cocaine exposure, cocaine-cue exposure, or the number of days to reach each ratio/infusion criterion between the 5- and 90-s groups.Total drug intake (panel A), number of cue-cocaine pairings (panel B) and days to reach ratio/infusion criteria (panel C) in the 5- and 90-s groups. Rats were required to meet the FR 1 and FR 2 criteria as well as infusion criteria 10–15 for 2 days each, and to meet infusion criterion 20 for 21 days. Values are mean ± SEM. n's = 6–7/group. s, seconds. CS, conditioned stimulus; UCS; unconditioned stimulus. FR; fixed ratio.

Mentions:
In experiment 2, rats were trained to nose-poke for cocaine delivered either over 5 or 90 s, with an 85-s time out period for the 5-s group, first under an FR 1 schedule, and then under FR 2. Acquisition criteria were defined as taking ≥5 infusions/session, at regular intervals throughout the session. Acquisition criteria had to be met for two consecutive days under each ratio schedule. Next, rats were allowed to self-administer cocaine infusions delivered either over 5 or 90 s and accompanied by light cues. During this phase, the rats were required to meet a criterion of 10 and then 15 infusions/session, for 2 consecutive days each, and then an infusion criterion of 20 for 21 days. Figure 5 shows the total amount of cocaine consumed (A), the total number of cue-cocaine pairings earned (B) and the number of days to reach each ratio and infusion criterion (C) by rats in the 5- and 90-s groups. There was no group difference in the total quantity of cocaine consumed [(A), t(11) = 0.19, p = 0.85] or the total number of cue-cocaine pairings earned [(B), t(11) = 0.24, p = 0.82]. In addition, there were no group differences in the mean ± SEM number of days to meet each ratio and infusion criterion [(C), F(1, 11) = 0.58, p = 0.46].

Bottom Line:
Rats in both the 5- and 90-second groups pressed more on the active versus inactive lever following extensive (24 sessions) but not following limited (3 sessions) self-administration training.There were no group differences in this behaviour.However, the rewarding properties of the cues were not "forgotten" because on withdrawal days 32-33, amphetamine selectively enhanced active-lever pressing, and did so to a similar extent in both groups.

ABSTRACTThe faster drugs of abuse reach the brain, the more addictive they can be. It is not known why this is. Environmental stimuli associated with drugs can promote the development and persistence of addiction by invigorating and precipitating drug-seeking behaviour. We determined, therefore, whether cues associated with the self-administration of rapidly delivered cocaine (injected intravenously over 5 versus 90 seconds) would acquire greater conditioned rewarding properties, as assessed by the performance of an operant response reinforced solely by the cues. Rats nose-poked for intravenous cocaine infusions delivered either over 5 or 90 seconds. Discrete visual cues accompanied each infusion. The rats could then press a lever to obtain the cues--now a conditioned reward--or an inactive lever. Rats in both the 5- and 90-second groups pressed more on the active versus inactive lever following extensive (24 sessions) but not following limited (3 sessions) self-administration training. There were no group differences in this behaviour. Following withdrawal from cocaine self-administration, lever discrimination progressively abated in both groups and was lost by withdrawal day 30. However, the rewarding properties of the cues were not "forgotten" because on withdrawal days 32-33, amphetamine selectively enhanced active-lever pressing, and did so to a similar extent in both groups. Thus, cues paired with rapid or slower cocaine delivery acquire similar conditioned rewarding properties. We conclude, therefore, that the rapid delivery of cocaine to the brain promotes addiction by mechanisms that might not involve a greater ability of drug cues to control behaviour.